Publication

The relevance of K-i calculation for bi-substrate enzymes illustrated by kinetic evaluation of a novel lysine (K) acetyltransferase 8 inhibitor

Wapenaar, H., van den Bosch, T., Leus, N. G. J., van der Wouden, P. E., Eleftheriadis, N., Hermans, J., Hailu, G. S., Rotili, D., Mai, A., Domling, A., Bischoff, R., Haisma, H. J. & Dekker, F. J., 18-Aug-2017, In : European Journal of Medicinal Chemistry. 136, p. 480-486 7 p.

Research output: Contribution to journalArticleAcademicpeer-review

APA

Wapenaar, H., van den Bosch, T., Leus, N. G. J., van der Wouden, P. E., Eleftheriadis, N., Hermans, J., Hailu, G. S., Rotili, D., Mai, A., Domling, A., Bischoff, R., Haisma, H. J., & Dekker, F. J. (2017). The relevance of K-i calculation for bi-substrate enzymes illustrated by kinetic evaluation of a novel lysine (K) acetyltransferase 8 inhibitor. European Journal of Medicinal Chemistry, 136, 480-486. https://doi.org/10.1016/j.ejmech.2017.05.015

Author

Wapenaar, Hannah ; van den Bosch, Thea ; Leus, Niek G. J. ; van der Wouden, Petra E. ; Eleftheriadis, Nikolaos ; Hermans, Jos ; Hailu, Gebremedhin Solomon ; Rotili, Dante ; Mai, Antonello ; Domling, Alexander ; Bischoff, Rainer ; Haisma, Hidde J. ; Dekker, Frank J. / The relevance of K-i calculation for bi-substrate enzymes illustrated by kinetic evaluation of a novel lysine (K) acetyltransferase 8 inhibitor. In: European Journal of Medicinal Chemistry. 2017 ; Vol. 136. pp. 480-486.

Harvard

Wapenaar, H, van den Bosch, T, Leus, NGJ, van der Wouden, PE, Eleftheriadis, N, Hermans, J, Hailu, GS, Rotili, D, Mai, A, Domling, A, Bischoff, R, Haisma, HJ & Dekker, FJ 2017, 'The relevance of K-i calculation for bi-substrate enzymes illustrated by kinetic evaluation of a novel lysine (K) acetyltransferase 8 inhibitor', European Journal of Medicinal Chemistry, vol. 136, pp. 480-486. https://doi.org/10.1016/j.ejmech.2017.05.015

Standard

The relevance of K-i calculation for bi-substrate enzymes illustrated by kinetic evaluation of a novel lysine (K) acetyltransferase 8 inhibitor. / Wapenaar, Hannah; van den Bosch, Thea; Leus, Niek G. J.; van der Wouden, Petra E.; Eleftheriadis, Nikolaos; Hermans, Jos; Hailu, Gebremedhin Solomon; Rotili, Dante; Mai, Antonello; Domling, Alexander; Bischoff, Rainer; Haisma, Hidde J.; Dekker, Frank J.

In: European Journal of Medicinal Chemistry, Vol. 136, 18.08.2017, p. 480-486.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

Wapenaar H, van den Bosch T, Leus NGJ, van der Wouden PE, Eleftheriadis N, Hermans J et al. The relevance of K-i calculation for bi-substrate enzymes illustrated by kinetic evaluation of a novel lysine (K) acetyltransferase 8 inhibitor. European Journal of Medicinal Chemistry. 2017 Aug 18;136:480-486. https://doi.org/10.1016/j.ejmech.2017.05.015


BibTeX

@article{5ea8f87744074f9f8a2513eb8a3e4e43,
title = "The relevance of K-i calculation for bi-substrate enzymes illustrated by kinetic evaluation of a novel lysine (K) acetyltransferase 8 inhibitor",
abstract = "Histone acetyltransferases (HATs) are important mediators of epigenetic post-translational modifications of histones that play important roles in health and disease. A disturbance of these modifications can result in disease states, such as cancer or inflammatory diseases. Inhibitors of HATs (HATi) such as lysine (K) acetyltransferase 8 (KAT8), could be used to study the epigenetic processes in diseases related to these enzymes or to investigate HATs as therapeutic targets. However, the development of HATi is challenged by the difficulties in kinetic characterization of HAT enzymes and their inhibitors to enable calculation of a reproducible inhibitory potency. In this study, a fragment screening approach was used, enabling identification of 4-amino-1-naphthol, which potently inhibited KAT8. The inhibitor was investigated for enzyme inhibition using kinetic and calorimetric binding studies. This allowed for calculation of the K-i values for both the free enzyme as well as the acetylated intermediate. Importantly, it revealed a striking difference in binding affinity between the acetylated enzyme and the free enzyme, which could not be revealed by the IC50 value. This shows that kinetic characterization of inhibitors and calculation of K-i values is crucial for determining the binding constants of HAT inhibitors. We anticipate that more comprehensive characterization of enzyme inhibition, as described here, is needed to advance the field of HAT inhibitors. (C) 2017 Elsevier Masson SAS. All rights reserved.",
keywords = "Histone acetyltransferases, KAT8, Fragment screening, Histone acetylation, Inhibitor, Enzyme kinetics, ASSAY INTERFERENCE COMPOUNDS, MSL COMPLEX, MOF, ACETYLATION, MECHANISMS, DISTINCT, PAINS",
author = "Hannah Wapenaar and {van den Bosch}, Thea and Leus, {Niek G. J.} and {van der Wouden}, {Petra E.} and Nikolaos Eleftheriadis and Jos Hermans and Hailu, {Gebremedhin Solomon} and Dante Rotili and Antonello Mai and Alexander Domling and Rainer Bischoff and Haisma, {Hidde J.} and Dekker, {Frank J.}",
year = "2017",
month = aug,
day = "18",
doi = "10.1016/j.ejmech.2017.05.015",
language = "English",
volume = "136",
pages = "480--486",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "ELSEVIER MASSON, CORPORATION OFFICE",

}

RIS

TY - JOUR

T1 - The relevance of K-i calculation for bi-substrate enzymes illustrated by kinetic evaluation of a novel lysine (K) acetyltransferase 8 inhibitor

AU - Wapenaar, Hannah

AU - van den Bosch, Thea

AU - Leus, Niek G. J.

AU - van der Wouden, Petra E.

AU - Eleftheriadis, Nikolaos

AU - Hermans, Jos

AU - Hailu, Gebremedhin Solomon

AU - Rotili, Dante

AU - Mai, Antonello

AU - Domling, Alexander

AU - Bischoff, Rainer

AU - Haisma, Hidde J.

AU - Dekker, Frank J.

PY - 2017/8/18

Y1 - 2017/8/18

N2 - Histone acetyltransferases (HATs) are important mediators of epigenetic post-translational modifications of histones that play important roles in health and disease. A disturbance of these modifications can result in disease states, such as cancer or inflammatory diseases. Inhibitors of HATs (HATi) such as lysine (K) acetyltransferase 8 (KAT8), could be used to study the epigenetic processes in diseases related to these enzymes or to investigate HATs as therapeutic targets. However, the development of HATi is challenged by the difficulties in kinetic characterization of HAT enzymes and their inhibitors to enable calculation of a reproducible inhibitory potency. In this study, a fragment screening approach was used, enabling identification of 4-amino-1-naphthol, which potently inhibited KAT8. The inhibitor was investigated for enzyme inhibition using kinetic and calorimetric binding studies. This allowed for calculation of the K-i values for both the free enzyme as well as the acetylated intermediate. Importantly, it revealed a striking difference in binding affinity between the acetylated enzyme and the free enzyme, which could not be revealed by the IC50 value. This shows that kinetic characterization of inhibitors and calculation of K-i values is crucial for determining the binding constants of HAT inhibitors. We anticipate that more comprehensive characterization of enzyme inhibition, as described here, is needed to advance the field of HAT inhibitors. (C) 2017 Elsevier Masson SAS. All rights reserved.

AB - Histone acetyltransferases (HATs) are important mediators of epigenetic post-translational modifications of histones that play important roles in health and disease. A disturbance of these modifications can result in disease states, such as cancer or inflammatory diseases. Inhibitors of HATs (HATi) such as lysine (K) acetyltransferase 8 (KAT8), could be used to study the epigenetic processes in diseases related to these enzymes or to investigate HATs as therapeutic targets. However, the development of HATi is challenged by the difficulties in kinetic characterization of HAT enzymes and their inhibitors to enable calculation of a reproducible inhibitory potency. In this study, a fragment screening approach was used, enabling identification of 4-amino-1-naphthol, which potently inhibited KAT8. The inhibitor was investigated for enzyme inhibition using kinetic and calorimetric binding studies. This allowed for calculation of the K-i values for both the free enzyme as well as the acetylated intermediate. Importantly, it revealed a striking difference in binding affinity between the acetylated enzyme and the free enzyme, which could not be revealed by the IC50 value. This shows that kinetic characterization of inhibitors and calculation of K-i values is crucial for determining the binding constants of HAT inhibitors. We anticipate that more comprehensive characterization of enzyme inhibition, as described here, is needed to advance the field of HAT inhibitors. (C) 2017 Elsevier Masson SAS. All rights reserved.

KW - Histone acetyltransferases

KW - KAT8

KW - Fragment screening

KW - Histone acetylation

KW - Inhibitor

KW - Enzyme kinetics

KW - ASSAY INTERFERENCE COMPOUNDS

KW - MSL COMPLEX

KW - MOF

KW - ACETYLATION

KW - MECHANISMS

KW - DISTINCT

KW - PAINS

U2 - 10.1016/j.ejmech.2017.05.015

DO - 10.1016/j.ejmech.2017.05.015

M3 - Article

C2 - 28527406

VL - 136

SP - 480

EP - 486

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -

ID: 46895302